Carla Pelusi

Obesity and the polycystic ovary syndrome

The polycystic ovary syndrome (PCOS) is a condition characterized by hyperandrogenism and chronic oligo-anovulation. However, many features of the metabolic syndrome are inconsistently present in the majority of women with PCOS. Approximately 50% of PCOS women are overweight or obese and most of them have the abdominal phenotype. Obesity may play a pathogenetic role in the development of the syndrome in susceptible individuals. In fact, insulin possesses true gonadotrophic function and an increased insulin availability at the level of ovarian tissue may favour excess androgen synthesis. Obesity, particularly the abdominal phenotype, may be partly responsible for insulin resistance and associated hyperinsulinemia in women with PCOS. Therefore, obesity-related hyperinsulinemia may play a key role in favouring hyperandrogenism in these women. Other factors such as increased estrogen production rate, increased activity of the opioid system and of the hypothalamic-pituitary-adrenal axis, decreased sex hormone binding globulin synthesis and, possibly, high dietary lipid intake, may be additional mechanisms by which obesity favours the development of hyperandrogenism in PCOS. Irrespective of the pathogenetic mechanism involved, obese PCOS women have more severe hyperandrogenism and related clinical features (such as hirsutism, menstrual abnormalities and anovulation) than normal-weight PCOS women. This picture tends to be more pronounced in obese PCOS women with the abdominal phenotype.Body weight loss is associated with beneficial effects on hormones, metabolism and clinical features. A further clinical and endocrinological improvement can also be achieved by adding insulin-sensitizing agents and/or antiandrogens to weight reduction programmes. These obviously emphasize the role of obesity in the pathophysiology of PCOS.

Accuracy of three-dimensional ultrasound in diagnosis and classification of congenital uterine anomalies

OBJECTIVE To assess the accuracy of three-dimensional (3D) ultrasound in the diagnosis of congenital uterine anomalies. DESIGN Prospective study. SETTING University hospital. PATIENT(S) Nulliparae with three or more consecutive miscarriages. INTERVENTION(S) All women underwent 3D transvaginal ultrasound study of the uterine cavity. MAIN OUTCOME MEASURE(S) Women with negative ultrasound findings subsequently underwent office hysteroscopy, whereas a combined laparoscopic-hysteroscopic assessment was performed in cases of suspected Müllerian anomaly. RESULT(S) A specific Müllerian malformation was sonographically diagnosed in 54 women of the 284 included in the study group. All negative ultrasound findings were confirmed at office hysteroscopy. Among the women with abnormal ultrasound findings, the presence of a Müllerian anomaly was endoscopically confirmed in all. Concordance between ultrasound and endoscopy around the type of anomaly was verified in 52 cases, including all those with septate uterus and two out of three with bicornuate uterus. CONCLUSION(S) Volume transvaginal ultrasound appears to be extremely accurate for the diagnosis and classification of congenital uterine anomalies and may conveniently become the only mandatory step in the assessment of the uterine cavity in patients with a history of recurrent miscarriage.

Impaired Follicle Development and Infertility in Female Mice Lacking Steroidogenic Factor 1 in Ovarian Granulosa Cells

Abstract The nuclear receptor steroidogenic factor 1 (SF-1 [officially designated NR5A1]) is essential for fetal gonadal development, but its roles in postnatal ovarian function are less well defined. Herein, we have extended our analyses of knockout (KO) mice with markedly decreased SF-1 expression in granulosa cells. As described, these SF-1 KO mice had hypoplastic ovaries that contained a decreased number of follicles and lacked corpora lutea. In the present study, we showed that SF-1 KO mice exhibited abnormal estrous cycles, were infertile, and released significantly fewer oocytes in response to a standard superovulation regimen. Moreover, they had blunted induction of plasma estradiol in response to gonadotropins. The granulosa cell-specific SF-1 KO also significantly affected ovarian expression of putative SF-1 target genes. Consistent with their decreased follicle number, these mice had reduced ovarian expression of anti-müllerian hormone (Amh), which correlates with the reserve pool of ovarian follicles, as well as decreased gonadotropin-induced ovarian expression of aromatase (Cyp19a1) and cyclin D2 (Ccnd2). In contrast, perhaps because of their abnormal cyclicity, SF-1 KO ovaries had higher basal expression of inhibin-alpha. They also had decreased immunoreactivity for genes related to proliferation (Ccnd2 and Mki67 [also known as Ki67]) and increased expression of Cdkn1b, also known as p27, which inhibits cyclin-dependent kinases, arguing for a role of SF-1 in granulosa cell proliferation. These findings demonstrate that SF-1 has a key role in female reproduction via essential actions in granulosa cells.

Effect of Long‐Term Testosterone Administration on the Endometrium of Female‐to‐Male (FtM) Transsexuals

INTRODUCTION Long term safety of testosterone (T) administration in women is still unknown. In particular few and discordant data exists on the effects of T on the endometrium. AIM The aim of this study was to investigate the effects of long-term T treatment on endometrium histology and proliferation in female to male transsexual subjects (FtM). We compared these endometria with those of young women in the proliferative phase (PM) of the cycle and with those of post menopausal women (M). METHOD Endometrial samples from 27 FtM treated with T (intramuscular injection of 100 mg Testoviron Depot /10 days for at least one year), 30 M undergoing vaginal hysterectomy, and 13 PM undergoing hysteroscopy for infertility problems were collected. Endometrial proliferation was evaluated on the basis of histopathology and expression of the proliferation marker Ki-67. Both M and PM women had not received any hormonal treatment for at least one year. MAIN OUTCOME MEASURE Circulating total testosterone (TT), estradiol (E), progesterone (P), insulin and glucose levels were measured in FtM and PM subjects. RESULTS FtM had received T for 33.6 +/- 21.3 months (mean +/- SD). In FtM subjects, histological analysis found inactive endometrium similar to the atrophic menopausal endometrium. The expression of Ki-67 in the glands, stroma and glands and stroma together was significantly (p < 0.0005) lower in FtM than in PM women and was similar in the FtM and M groups. Small polyps were detected in 5 of the 27 FtM subjects. CONCLUSIONS In conclusion our data suggest that exogenous T administration does not stimulate endometrial proliferation in FtM transsexuals and indeed may have atrophic effects.

Effects of Three Different Testosterone Formulations in Female-to-Male Transsexual Persons

INTRODUCTION Gender dysphoria is characterized by a strong discomfort with the gender assigned at birth and the urge to live as a member of the opposite gender. The acquisition of phenotypic features of the desired gender requires the use of cross-sex hormones. Female-to-male (FtM) transsexual persons are treated with testosterone to induce virilization. AIM The aim of the study was to assess the effects of three different testosterone formulations on body weight and composition and metabolic and bone parameters. METHODS Forty-five FtM transsexuals were randomly assigned to receive testoviron depot (i.m.: 100 mg/10 days; n = 15), testosterone gel (50 mg/die; n = 15), and testosterone undecanoate (i.m.: 1,000 mg every 6 weeks for the first 6 weeks and then every 12 weeks, n = 15). FtM individuals were studied before, at week 30, and at week 54 of testosterone treatment. MAIN OUTCOME MEASURES Anthropometric, metabolic, bone, hematological, and biochemical parameters were evaluated at baseline and after 12 months of treatment. RESULTS Lean body mass significantly increased and fat mass decreased in all groups. No modifications were reported in fasting insulin and insulin sensitivity index. High-density plasma lipoprotein levels declined significantly and low-density lipoprotein concentrations increased significantly in the three groups. The activated partial thromboplastin time and factor I did not change while prothrombin time significantly increased in all groups. At week 54, all subjects were amenorrheic and time to amenorrhea did not differ between the three groups. Current general life satisfaction was increased in all subjects after 1 year of treatment. CONCLUSIONS One-year testosterone administration in FtM transsexuals appears to be very safe with no differences among the testosterone formulations used. Our study is preliminary, and the detection of subtle or long-term differences in the effects of the three formulations may require further larger and longer term studies in this and other populations.

Polycystic Ovary Syndrome in Adolescents

Polycystic ovary syndrome is a heterogeneous clinical syndrome, which has been defined as the association of hyperandrogenism with chronic anovulation in women without specific adrenal and pituitary gland disease. A family history of polycystic ovary syndrome may be present in a subset of patients; however, the genetic basis of the syndrome remains unclear. Most often, the age of onset is perimenarchal and it is characterized by the appearance of menstrual disturbances, hirsutism, acne, and more rarely, a male pattern of alopecia. In some cases, premature adrenarche may present as a precursor to the development of the syndrome. Polycystic ovary syndrome is also associated with metabolic disturbances, such as obesity and insulin resistance with hyperinsulinemia, for which the pathophysiological role in the development of the syndrome has been recognized.The therapeutic approaches to polycystic ovary syndrome include lifestyle modifications, dietary-induced weight loss, insulin-sensitizing agents, antiandrogens, and oral contraceptives. These treatments may improve the clinical manifestations of excess androgen production and normalize menses in many adolescents and young women with polycystic ovary syndrome. Early recognition of the syndrome and thus, early treatment, may prevent and possibly ameliorate all the symptoms and the potential later development of metabolic and cardiovascular complications.

The Impairment of Sexual Function Is Less Distressing for Menopausal than for Premenopausal Women

INTRODUCTION Menopause requires psychological and physical adjustments because of the occurring significant hormonal changes. Sexuality is one of the aspects that undergoes the most profound modifications. Preliminary data suggest that sometimes women do not regard sexual changes as problematic and often readjust their life and relationship according to their new physical status. AIM The aim of our study was to evaluate sexual function and the way women feel by comparing healthy postmenopausal and premenopausal women. METHODS One hundred menopausal (M) and 100 premenopausal (pM) healthy women were asked to complete anonymous questionnaires to assess sexual function and stress related to sexual activity. MAIN OUTCOME MEASURES Female Sexual Function Index (FSFI), Female Sexual Distress Scale (FSDS) were completed by M and pM women. Results. Medium FSFI score was 20.5 +/- 9.6 and 26.4 +/- 7.7 (P < 0.0005) and medium FSDS score was 12.1 +/- 11.7 (95% CI 9.7-14.4) and 11.3 +/- 10.2 (P = 0.917) for M and pM women, respectively. Twenty-five of the 69 M women and 20 of the 31 pM women with a pathological score in the FSFI questionnaire scored higher than 15 in the FSDS (P < 0.0005). The overall prevalence of sexual dysfunction was 20% and 25% (P = 0.5) in the M and pM women. CONCLUSIONS Our data confirm that menopause is associated with changes in sexual function that may be compatible with sexual dysfunction. However, personal distress caused by these changes in sexual life appears to be lower among menopausal women (36.2%) as compared with premenopausal women (64.5%). These data suggest that medical treatment for sexual health in menopause must be highly personalized and carefully prescribed.

Outcome of conservatively treated microinvasive squamous cell carcinoma of the uterine cervix during a 10-year follow-up.

Objective: To assess the rate, the cumulative proportion, and the predictors of cervical intraepithelial neoplasia grades 2-3 (CIN 2-3) and invasive disease during the follow-up of patients conservatively treated for microinvasive (stage Ia1-2) squamous cell carcinoma (MIC) of the uterine cervix. Methods: Two hundred thirty women (median age, 37 years; range, 20-69 years) conservatively treated for MIC were followed up for 10 years and analyzed for cumulative proportion of CIN 2-3/invasive disease. The multivariate survival analysis was used to assess the clinicopathological features predicting the development of CIN 2-3/SCC. Results: Of the 230 patients primarily treated by cone, 76 (33%) underwent hysterectomy as the immediate retreatment, and 13 had a residual disease. The remaining 154 women were subjected to posttreatment follow-up. The depth of stromal invasion was strongly associated with the prevalence of positive lymph nodes and lymphovascular space invasion (LVSI). The detection rate of CIN 2-3/SCC was stable at the first 2 visits (6.5% and 6.9%) and dropped thereafter. The cumulative proportion of patients whose conditions were diagnosed as CIN 2-3/carcinoma was 0.07, 0.09, 0.15, and 0.19 at 6, 12, 36, and 120 months, respectively. In multivariate survival analysis, involvement of 4 quadrants (odds ratio [OR], 5.8), LVSI (OR, 4.5), and cone margin involvement (OR, 5.6) were significant independent predictors of CIN 2-3/SCC after treatment. The upper age tertile (42-69 years) was an independent protective factor (OR, 0.3; 95% confidence interval, 0.1-0.9). Conclusions: A close, long-term surveillance should be scheduled for the MIC patients conservatively treated. Cone margin involvement, LVSI, and the number of quadrants involved on colposcopy are independent risk factors for disease persistence and/or progression to SCC.

Revisiting hyper- and hypo-androgenism by tandem mass spectrometry.

Modern endocrinology is living a critical age of transition as far as laboratory testing and biochemical diagnosis are concerned. Novel liquid chromatography—tandem mass spectrometry (LC-MS/MS) assays for steroid measurement in biological fluids have abundantly demonstrated their analytical superiority over immunometric platforms that until now have dominated the world of steroid hormones determination in clinical laboratories. One of the most useful applications of LC-MS/MS is in the hypogonadism and hyperandrogenism field: LC-MS/MS has proved particularly suitable for the detection of low levels of testosterone typical of women and children, and in general more reliable in accurately determining hypogonadal male levels. This technique also offers increased informative power by allowing multi-analytical profiles that give a more comprehensive picture of the overall hormonal asset. Several LC-MS/MS methods for testosterone have been published in the last decade, some of them included other androgen or more comprehensive steroid profiles. LC-MS/MS offers the concrete possibility of achieving a definitive standardization of testosterone measurements and the generation of widely accepted reference intervals, that will set the basis for a consensus on the diagnostic value of biochemical testing. The present review is aimed at summarizing technological advancements in androgen measurements in serum and saliva. We also provide a picture of the state of advancement of standardization of testosterone assays, of the redefinition of androgen reference intervals by novel assays and of studies using LC-MS/MS for the characterization and diagnosis of female hyperandrogenism and male hypogonadism.

Short-term modification of sex hormones is associated with changes in ghrelin circulating levels in healthy normal-weight men.

The aim of this study was to evaluate the effect of selective and short-term sex hormone modifications on ghrelin levels in normal-weight eugonadal men undergoing hormonal contraceptive treatments. Seven men received an oral progestin [cyproterone acetate (CPA) or dienogest (DNG)] 10 mg/day for 3 weeks (CPA-DNG group), 7 CPA orally 5 mg/day in association with testosterone enanthate (TE) im 200 mg/week for 8 weeks (CPA-TE group), and 7 placebo (PLAC) for 8 weeks (PLAC group). Anthropometry and blood levels of LH, FSH, testosterone, estradiol, glucose, insulin and total ghrelin were evaluated. At baseline, no parameters differed among the three groups. After treatment, LH and FSH decreased in both CPA-DNG and CPA-TE groups, whereas they did not change in the PLAC group. Testosterone and estradiol decreased in the CPA-DNG group to the hypogonadal range, increased in the CPA-TE group to supraphysiological concentrations and, as expected, remained unchanged in the PLAC group. Total ghrelin levels increased in the CPA-DNG, decreased in the CPA-TE and did not change in the PLAC group. Ns modifications in the other parameters were observed in any group, demonstrating that the short-term changes of circulating sex hormones are able to modify ghrelin levels. These data, therefore, suggest that sex steroids are important regulators of ghrelin in normal-weight healthy men too.